This invention relates to improved calibration reagents for water determination using the Karl Fischer reaction. More particularly, the invention relates to a formed tablet calibration standard-reagent for calibrating Karl Fischer reactions for determining water content in a substance, said reagent containing a first component, namely sodium tartrate dihydrate, and a second component, namely magnesium stearate.
Moisture measurement is valuable because the presence of water can adversely affect a variety of applications across multiple industries. Some examples include pharmaceutical drug stability; foodstuff storage quality; properties of oils (e.g. viscosity); and reduced chemical reaction yield (e.g. production of plastics). Moisture content determination is an evaluation criterion necessary for stability considerations of New Drug Applications. Accurate control and monitoring of moisture in these fields is often required by regulatory agencies and necessary to improve product quality.
A number of chromatographic, spectroscopic, electronic, thermal, and wet chemical methods have been used in the past to determine moisture levels (S. K. MacLeod, Anal. Chem., 1991, 63, 557A–565A). The most common of these are loss on drying (LOD), thermogravimetric analysis (TGA), gas chromatography using a thermal conductivity detector, and the Karl Fischer titration. Of these most common water content measurements, however, the Karl Fischer titration has become the method of choice and is now the approach most widely used in the determination of water content. The determination of moisture in materials such as liquids and solids by the Karl Fischer reaction is well known and widely used since it was first described by Karl Fischer in Angewandte Chemie 48, pages 394–396 (1935). Numerous publications have also described this technique for water determination, and reference is made to a general text by J. Mitchell, Jr. and D. M. Smith, entitled “Aquametry”, published by John Wiley and Sons, 1980. Reference is also made to a publication by E. Scholz entitled, “Karl Fischer Titration,” published by Springer Verlag in 1984.
In a Karl Fischer reaction, the water to be determined reacts with iodine on a quantitative basis and consequently, the amount of reacted iodine is a measure of the amount of water present in the sample. The reaction proceeds according to the following expression:H2O+SO2+I2=2H++2I−+SO3  (1)
The titration can be run in either protic or aprotic medium, with the protic medium seeing wider use due to higher sensitivity of the titer to sample and solvent composition (M. S. Kamat, R. A. Lodder and P. P. DeLuca, Pharmaceutical Research, 1989 6(11) 961–965.). The reaction in protic media (i.e., alcohol) involves sulfur dioxide reacting with the alcohol to produce an alkyl sulfite in a buffered medium using an appropriate base to maintain the solution at the optimal pH. In a coulometric experiment, the iodine is generated electrically from iodine present in the cell. The electric efficiency of this method is generally 100%, and the amount of water in the sample is calculated from the number of moles of electrons used in the iodine generation. The components necessary to carry out this reaction have been formulated and are readily available as Karl Fischer reagents. These reagents are divided into two groups, single-component and two-component systems. In the single-component systems, all ingredients (iodine, buffer, SO2, and solvent) are in one solution. In the two-component systems, the “vessel” solution contains the buffer, SO2, and a solvent, while the “titrant” solution contains iodine in a suitable solvent.
Thus, Karl Fischer reagents are used in several types of analysis. A volumetric analysis using a volumetric reagent determines moisture by measuring the volume of the Karl Fischer reagent consumed during the analysis. A coulometric analysis using a coulometric reagent generates iodine by passing a current through the reagent and determines the moisture from the amount of current.
Analytical instrumentation, semi-automating the Karl Fischer assay, is most commonly used to conduct Karl Fischer titrations. Working medium (Methanol) is added to the titration vessel and conditioned to equilibrium (end point with a slight excess of reagent) with titrant. The weighed sample is then delivered into the vessel for titration to the same end point. The amount of water in the sample under test is determined using the reagent strength factor (based on instrument calibration with material of known water content) and the volume of reagent dispensed to reach equilibrium.
Examples, of instrumentation utilizing the Karl Fischer reaction for determination of water content comprise: 1) Volumetric Moisture Meter, Model KF-100, Mitsubishi Chemical Corporation; 2) Aquastar® Volumetric Titrator, Models V1B and V-200, EM Science; 3) Schott Titroline KF, Schott; 4) Metrohm® & Volumetric Karl Fischer Titration Systems, Models 701, 784, 758, 756, Brinkmann Instruments, Incorporated; 5) Orion® Volumetric Karl Fischer Titrators, Models TURB02™ and AF8, Thermo Orion, Incorporated; and 6) Mettler-Toledo Titrators, Models DL53, DL55, DL58, Mettler-Toledo Corporation.
Accurate moisture content determination measurements using the Karl Fischer titration are contingent on the proper working order of the titration instrument and the chemical reactions. Successful moisture content determinations require that 1) equipment be in proper working order, 2) reagents be stable and not depleted, 3) moisture be excluded from the system, 4) the anodic reaction produce 100% current yield, 5) the cathodic reaction does not interfere with the titration, and 6) the reaction not be adversely affected by the sample matrix.
To assure that these criteria are being met, the quality of the analysis is checked against calibration standards containing known moisture content. The correct moisture content determination for the standards confirms that the Karl Fischer titration analysis is running properly, or indicates that a problem exists. A variety of materials have been proposed as standards for moisture content determinations. The principal requirements of these materials are 1) that they contain a stoichiometric amount of moisture that is stable over a wide range of temperature and humidity, 2) solubility in the Karl Fischer titration reagents, 3) ease of handling and storage, 4) availability, and 5) uniformity (M. S. Kamat, R. A. Lodder and P. P. DeLuca, Pharmaceutical Research, 1989, 6(11), 961–965.).
Many possible calibration standards for Karl Fischer determination of water have been described. These include: purified water, certified water standards (known water content determined by assay), Aluminum potassium sulfate, Ammonium oxalate, Citric acid, Ferric ammonium sulfate, Ferrous ammonium sulfate, Lactose, Oxalic acid, Potassium citrate, Potassium sodium tartrate, Potassium tartrate, sodium acetate, sodium bitartrate, sodium citrate, and sulfosalicylic acid (Neuss, J. D. Obrien, and M. G. Frediani, H. A., Analytical Chemistry, 23, 1332 [1951]).
Much effort has been given to making liquid water standard solutions less hygroscopic. These efforts have not been completely successful, as the water content of the solutions change after the septum over the solutions has been pierced several times. Water is a very good calibration reagent, but it is difficult to accurately dispense liquid water into the Karl Fischer titrator. When delivered by volume, the inaccuracies of the small amount delivered make it difficult to obtain an accurate value. A more accurate measurement is obtained when the liquid water is delivered by weight, but this again presents difficulties in dispensing the water into the titrator. Also, degradation and stability of the standard become relevant due to the special material handling characteristics that must be considered for certified liquid calibration media.
Use of sodium tartrate dihydrate in powder form as a calibration standard for KF reactions is known in the art (E. Scholz, Karl Fischer Titration-Determination of Water-Chemical Laboratory Practice, Springer-Verlag, N.Y. 1984, T. H. Beasley, H. W. Siegler, R. L. Charles and P. King, Anal. Chem., 1972, 44, 1833–1840). However, bulk powder calibration standards are difficult to manipulate, which can result in increased assay variability due to the ingress of ambient moisture and the residual standard unaccounted for during sample addition. Another problem with the sample transfer process of the prior art is dispensing the calibration standard material into the Karl Fischer titrator. When trying to pour the powder material through a funnel into the titrator, some material is lost into the atmosphere or adheres to the sampling funnel, and thus is not all dispensed into the titrator. To mitigate this detriment, weighing paper can be rolled to create a funnel, but this requires operator dexterity. In either case, during the transfer of the powder, the titrator is open to the atmosphere, and the length of time the vessel is open is inversely related to the accuracy of the determination. Therefore, the prior art method using powder calibration standards requires significant analyst time and creates variability in assay results.
Thus, in its prior art configuration, Karl Fischer titrations were affected by: 1) sample transfer time, 2) relative humidity in the laboratory, and 3) material lost in the material transfer. These factors make it desirable to have an improved calibration standard reagent. Such an improved reagent would result in reduced time to load the reagent, provide for more accurate and quantitative transfer, and have less fluctuation in water content, as compared to the prior art liquid and powder calibration standards.
Accordingly, it is an object of this invention to provide a formed tablet calibration standard-reagent for calibrating Karl Fischer reactions for determining water content in a substance. It is another object of this invention to provide an improved process for the determination of water in a sample using the Karl Fischer reaction, in which the calibration reagent that is employed is a formed tablet calibration standard-reagent. Said formed tablet calibration standard-reagent containing a first component, namely sodium tartrate dihydrate, and a second component, namely magnesium stearate.
A formed tablet calibration standard-reagent would fundamentally reduce variability in the Karl Fischer assay. Differences due to analyst technique would be minimized because standard addition is simplified and more consistent. Cumbersome use of a syringe and injection into the titration vessel would be replaced with a single hand transfer of the tablet to the vessel through the sample port. Titration methodology would remain the same in all other aspects with the exception of instrument calibration. A formed tablet calibration standard would remove the barriers posed by prior art standards which act to deter the automation of Karl Fischer determination of water content. An automated Karl Fischer assay employing a formed tablet calibration standard would dramatically increase productivity in Karl Fischer water determinations.
These and other objects, features, and advantages will be apparent from the following more particular description of the preferred embodiments of the invention.